Abstract
Rising antibiotic resistance urgently calls for the discovery and evaluation of novel antibiotic classes and unique antibiotic targets. The caseinolytic protease Clp emerged as an unprecedented target for antibiotic therapy 15 years ago when it was observed that natural product-derived acyldepsipeptide antibiotics (ADEP) dysregulated its proteolytic core ClpP towards destructive proteolysis in bacterial cells. A substantial database has accumulated since on the interaction of ADEP with ClpP, which is comprehensively compiled in this review. On the molecular level, we describe the conformational control that ADEP exerts over ClpP, the nature of the protein substrates degraded, and the emerging structure-activity-relationship of the ADEP compound class. On the physiological level, we review the multi-faceted antibacterial mechanism, species-dependent killing modes, the activity against carcinogenic cells, and the therapeutic potential of the compound class.
Highlights
Reviewed by: Thomas Dick, Hackensack Meridian Health, United States Walid A Houry, University of Toronto, Canada
The caseinolytic protease Clp emerged as an unprecedented target for antibiotic therapy 15 years ago when it was observed that natural product-derived acyldepsipeptide antibiotics (ADEP) dysregulated its proteolytic core ClpP towards destructive proteolysis in bacterial cells
We describe the conformational control that ADEP exerts over ClpP, the nature of the protein substrates degraded, and the emerging structure-activity-relationship of the ADEP compound class
Summary
The target of ADEP is ClpP, a fact confirmed in a range of different bacterial species. The experimental set-up did not allow differentiation between the extent of co-translational vs potential post-translational degradation (i.e., whether the fragments were generated from nascent chains or folded proteins), the fact that the ADEP-activated ClpP core had such a broad destructive potential on resting cells suggests that folded proteins can be attacked (Conlon et al, 2013). Α-helices previously embedded in the folded N-terminal domain are exposed and become vulnerable to proteolytic attack, followed by degradation of the entire protein (Silber et al, 2020) This process occurs at an equimolar ratio of ADEP to ClpP monomer. The molecular explanation for this differential targeting process and whether it might involve different levels of conformational control of ADEP over ClpP is still elusive (Silber et al, 2020)
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